VEGF-C, a Lymphatic Growth Factor, Is a RANKL Target Gene in Osteoclasts That Enhances Osteoclastic Bone Resorption through an Autocrine Mechanism

Zhang, Qian; Guo, Renhua; Lu, Yan; Zhao, Lan; Zhou, Quan; Schwarz, Edward M.; Huang, Jing; Chen, Di; Jin, Zhigang; Boyce, Brendan F.; Xing, Lianping

doi:10.1074/jbc.m708055200

Cited by 73 publications

(70 citation statements)

References 47 publications

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“…26 PIGF is a homologue of VEGF-C; both are RANKL targets and mediate RANKL activity. 27 We found, however, that VEGF-C was not able to support human osteoclast formation independent of M-CSF. RANKL enhances the expression of VEGF-C mRNA and overexpression of VEGF-C increases resorption activity four-fold.…”

Section: Discussionmentioning

confidence: 49%

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VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Taylor

Kashima

Knowles

et al. 2012

Laboratory Investigation

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Giant cell tumour of bone (GCTB) is a primary bone tumour that contains numerous very large, hyper-nucleated osteoclastic giant cells. Osteoclasts form from CD14 þ monocytes and macrophages in the presence of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). GCTB contains numerous growth factors, some of which have been reported to influence osteoclastogenesis and resorption. We investigated whether these growth factors are capable of substituting for M-CSF to support osteoclast formation from cultured human monocytes and whether they influence osteoclast cytomorphology and resorption. Vascular endothelial growth factor-A (VEGF-A), VEGF-D, FLT3 ligand (FL), placental growth factor (PlGF) and hepatocyte growth factor (HGF) supported RANKL-induced osteoclastogenesis in the absence of M-CSF, resulting in the formation of numerous TRAP þ multinucleated cells capable of lacunar resorption. Monocytes cultured in the presence of M-CSF, HGF, VEGF-A and RANKL together resulted in the formation of very large, hyper-nucleated (GCTB-like) osteoclasts that were hyper-resorptive. M-CSF and M-CSF substitute growth factors were identified immunohistochemically in GCTB tissue sections and these factors stimulated the resorption of osteoclasts derived from a subset of GCTBs. Our findings indicate that there are growth factors that are capable of substituting for M-CSF to induce human osteoclast formation and that these factors are present in GCTB where they influence osteoclast cytomorphology and have a role in osteoclast formation and resorption activity. The osteoclast is a multinucleated cell, which is formed from circulating mononuclear phagocyte precursors derived from the bone marrow. 1,2 It exhibits a number of specialised cytochemical and functional features, including the ability to carry out lacunar bone resorption. Increased osteoclast formation and activity is seen in a number of osteolytic bone and joint conditions, including notably giant cell tumour of bone (GCTB), a primary bone tumour, which contains numerous, very large, often hyper-nucleated osteoclastic giant cells that effect a considerable amount of bone resorption. 3,4 Osteoclast differentiation from monocyte or macrophage precursors requires the presence of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). 5 The importance of M-CSF in osteoclast formation is evidenced by the fact that in op/op osteopetrotic mice, which have a mutation in the M-CSF gene, very few osteoclasts are found in bone and there is markedly decreased bone resorption. 6,7 M-CSF promotes several aspects of osteoclastogenesis including the proliferation and fusion of osteoclast precursors as well as osteoclasts and the expression of the RANKL receptor by these cells. [8][9][10] The effect of M-CSF on mature osteoclast resorption activity is controversial with both a decrease and increase in lacunar resorption being reported. [11][12][13] Although bone resorption is gre...

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Section: Discussionmentioning

confidence: 49%

“…RANKL enhances the expression of VEGF-C mRNA and overexpression of VEGF-C increases resorption activity four-fold. 27 VEGF-C binds to VEGFR2 and VEGFR3, and osteoclasts have been shown to express VEGFR3; it is possible that VEGF-C mediates its effects largely through VEGFR2 rather than VEGFR3.…”

Section: Discussionmentioning

confidence: 99%

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Taylor

Kashima

Knowles

et al. 2012

Laboratory Investigation

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“…WT BM cells were cultured with M-CSF for 2 days on bone slices to generate OCPs and then CQ (5 μM) and RANKL were added. Cells were fixed and stained for TRAP activity to allow counting of OCs, which were then removed; bone slices were stained with 0.5% toluidine blue to visualize resorption pits, as described (67).…”

Section: Relb Is Required For Rankl-induced Traf3 Lysosomal Degradatimentioning

confidence: 99%

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

Xiu¹,

Xu²,

Zhao³

et al. 2013

J. Clin. Invest.

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139

180

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The cytokines RANKL and TNF activate NF-κB signaling in osteoclast precursors (OCPs) to induce osteoclast (OC) formation. Conversely, TNF can limit OC formation through NF-κB p100, which acts as an inhibitor, and TNF receptor-associated receptor 3 (TRAF3); however, a role for TRAF3 in RANKL-mediated OC formation is unknown. We found that TRAF3 limits RANKL-induced osteoclastogenesis by suppressing canonical and noncanonical NF-κB signaling. Conditional OC-specific Traf3-KO (cKO) mice had mild osteoporosis and increased OC formation. RANKL induced TRAF3 degradation via the lysosome/autophagy system. The autophagy/lysosome inhibitor chloroquine reduced RANKL-induced OC formation and function by increasing TRAF3 expression in OCPs in vitro and in vivo. Although chloroquine had no effect on basal bone resorption, it inhibited parathyroid hormone-and ovariectomy-induced OC activation in WT, but not cKO, mice. Deletion of the transcription factor gene Relb resulted in increased TRAF3 expression in OCPs, which was associated with decreased RANKL-induced TRAF3 degradation. RelB directly increased expression of BECN1, a key autophagy regulator, by binding to its promoter. These data indicate that autophagic/lysosomal degradation of TRAF3 is an important step in RANKL-induced NF-κB activation in OCPs. Furthermore, treatments that increase TRAF3 levels in OCPs, including pharmacological inhibition of its degradation with compounds such as chloroquine, may limit bone destruction in common bone diseases.

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“…RANKL also stimulates osteoclasts and osteoclast precursors to produce and release the lymphatic growth factor, vascular endothelial growth factor C (VEGF-C), which further increases osteoclastogenesis and is also associated with increased lymphangiogenesis. (67) BONE FORMATION…”

Section: Other Novel Concepts Of Bone Resorptionmentioning

confidence: 99%

Targeting Bone Remodeling for the Treatment of Osteoporosis: Summary of the Proceedings of an ASBMR Workshop

Bilezikian

Matsumoto

Bellido

et al. 2009

Journal of Bone and Mineral Research

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VEGF-C, a Lymphatic Growth Factor, Is a RANKL Target Gene in Osteoclasts That Enhances Osteoclastic Bone Resorption through an Autocrine Mechanism

Cited by 73 publications

References 47 publications

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

Targeting Bone Remodeling for the Treatment of Osteoporosis: Summary of the Proceedings of an ASBMR Workshop

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